Objectives: To evaluate the efficiency of injectable platelet-rich fibrin (i-PRF) in accelerating canine tooth movement and to examine levels of the matrix metalloproteinase-8 (MMP-8), interleukin-1b (IL-1b), receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand (RANKL), and osteoprotegerin (OPG) in the gingival crevicular fluid during orthodontic treatment. Materials and Methods: Twenty patients (mean age ¼ 21.4 6 2.9 years) with Class II Division 1 malocclusion were included in a split-mouth study. The treatment plan for all patients was extraction of maxillary first premolars followed by canine distalization with closed-coil springs using 150 g of force on each side. The study group received i-PRF two times, with a 2-week interval, on one side of the maxilla. The contralateral side served as the control and did not receive i-PRF. Maxillary canine tooth movement was measured at five time points (T1–T5) on each side. Also, the activity of inflammatory cytokines was evaluated at three time points in the gingival crevicular fluid samples. Results: There was a significant difference in canine tooth movement between the two groups (P, .001). i-PRF significantly increased the rate of tooth movement, and stimulation in the levels of inflammatory cytokines supported this result (P, .001). The levels of cytokines changed in both groups between T1 and T2. The IL-1b, MMP8, and RANKL values were significantly increased in the study group compared with the control group, while the OPG values were significantly decreased. Conclusions: i-PRF-facilitated orthodontics is an effective and safe treatment modality to accelerate tooth movement, and this method can help shorten orthodontic treatment duration. (Angle Orthod. 2021;91:285–292.)